PMID- 18025411
OWN - NLM
STAT- MEDLINE
DCOM- 20080317
LR  - 20111117
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 57
IP  - 2
DP  - 2008 Feb
TI  - In vivo effects of insulin and free fatty acids on matrix metalloproteinases in 
      rat aorta.
PG  - 476-83
AB  - OBJECTIVE: Obesity is associated with insulin resistance, hyperinsulinemia, 
      elevated plasma free fatty acid (FFA), and increased risk for atherosclerotic 
      vascular disease (ASVD). A part of this increased risk may be due to enhanced 
      activation of matrix metalloproteinases (MMPs). Here, we have examined the 
      effects of physiologically elevated levels of insulin and FFA on three MMPs and 
      their inhibitors (tissue inhibitors of MMP [TIMPs]) in aortic tissue of male rats 
      during euglycemic-hyperinsulinemic clamping. RESEARCH DESIGN AND METHODS: 
      Four-hour euglycemic-hyperinsulinemic clamps with infusion of saline/glycerol, 
      lipid/heparin, or insulin with or without lipid/heparin were performed in alert 
      unrestrained male rats. RESULTS: Hyperinsulinemia increased MMP-2 ( approximately 
      6-fold), MMP-9 ( approximately 13-fold), membrane type 1-MMP (MT1-MMP; 
      approximately 8-fold) (all Western blots), and gelatinolytic activity 
      (zymography) of MMP-2 (2-fold), while not affecting TIMP-1 and TIMP-2. Insulin 
      increased IRS-1-associated PI 3-kinase (PI3K), extracellular signal-regulated 
      kinases 1/2 (ERK1/2), and c-jun NH(2)-terminal kinase (JNK) (by Western blots 
      with phospho-specific antibodies). FFA augmented the insulin-mediated increases 
      in MMP-2 (from approximately 6- to approximately 11-fold), MMP-9 (from 
      approximately 3- to approximately 23-fold), MT1-MMP (from approximately 8- to 
      approximately 20-fold), MMP-2 gelatinolytic activity (from 2- to 3-fold), and JNK 
      and p38 mitogen-activated protein kinase (MAPK) activities but decreased 
      insulin-mediated activation of PI3K and ERK1/2. Raising FFA without raising 
      insulin affected neither MMPs nor TIMPs. CONCLUSIONS: FFA augmented insulin 
      stimulation of the MMP/TIMP balance of three proatherogenic MMPs and increased 
      activities of two MAPKs (JNK and p38 MAPK), both of which are known to stimulate 
      the production of proinflammatory cytokines. This may, over time, increase 
      degradation of extracellular matrix and together with inflammatory changes 
      promote development of ASVD.
FAU - Boden, Guenther
AU  - Boden G
AD  - Temple University Hospital, 3401 North Broad St., Philadelphia, PA 19140, USA. 
      bodengh@tuhs.temple.edu
FAU - Song, Weiwei
AU  - Song W
FAU - Pashko, Laura
AU  - Pashko L
FAU - Kresge, Karen
AU  - Kresge K
LA  - eng
GR  - HL-0733267/HL/NHLBI NIH HHS/United States
GR  - R01-DK066003/DK/NIDDK NIH HHS/United States
GR  - R01-DK58895/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071119
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Insulin)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Animals
MH  - Aorta/drug effects/*enzymology
MH  - Catheters, Indwelling
MH  - Fatty Acids, Nonesterified/administration & dosage/*pharmacology
MH  - Glucose Clamp Technique
MH  - Hyperinsulinism/enzymology/metabolism
MH  - Insulin/administration & dosage/*pharmacology
MH  - Male
MH  - Matrix Metalloproteinases/drug effects/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tissue Inhibitor of Metalloproteinase-1/drug effects
MH  - Tissue Inhibitor of Metalloproteinase-2/drug effects
EDAT- 2007/11/21 09:00
MHDA- 2008/03/18 09:00
CRDT- 2007/11/21 09:00
PHST- 2007/11/21 09:00 [pubmed]
PHST- 2008/03/18 09:00 [medline]
PHST- 2007/11/21 09:00 [entrez]
AID - db07-1261 [pii]
AID - 10.2337/db07-1261 [doi]
PST - ppublish
SO  - Diabetes. 2008 Feb;57(2):476-83. doi: 10.2337/db07-1261. Epub 2007 Nov 19.